From the Atherosclerosis Research Center (P.K.S., S.K., M.C.F., B.C.),
Division of Cardiology, Burns and Allen Research Institute, Cedars-Sinai
Medical Center and UCLA School of Medicine, Los Angeles, Calif; King Gustav V
Research Institute (J.N., A.H., F.K.), Karolinska Hospital, Stockholm, Sweden;
and Pharmacia-Upjohn (H.A., J.J.), Stockholm, Sweden.
Correspondence to Prediman K. Shah, MD, Cedars-Sinai Medical Center, Room 5347, 8700 Beverly Boulevard, Los Angeles, CA 90048. E-mail shahp{at}csmc.edu
Background—We previously reported
marked inhibitory effects of recombinant apolipoprotein
(apo) A-IMilano/phospholipid complex
(A-IMilano/PC) on neointimal lesions in
balloon-injured iliofemoral arteries of
hypercholesterolemic rabbits. In this study, we tested
the hypothesis that apo A-IMilano/PC would inhibit aortic
atherosclerosis in apo E–deficient mice.
Methods and Results—Thirty-five apo E–deficient mice fed a
high-cholesterol diet were included in the study. Control
mice were killed at 20 (n=8) or 25 (n=7) weeks. Treated mice received
18 injections of either 40 mg/kg apo A-IMilano/PC (n=15) or
PC only (n=5) intravenously every other day from 20 weeks
until death at 25 weeks. Aortic atherosclerosis was
identified with Sudan IV staining. Lipid and macrophage
contents of the aortic sinus plaques were measured after oil-red O and
Mac-1 antibody staining, respectively, and quantified with computed
morphometry. In control mice, from 20 to 25 weeks, aortic
atherosclerosis increased by 59% (11±1% versus
17±5% of the aortic surface, P=.002), and lipid
content increased by 45% (22±8% versus 32±6% of plaque area,
P=.02) without a significant change in
macrophage content (10.8±2% versus 13.2±6%). Compared with
20-week-old untreated control mice, PC only–treated mice at 25 weeks
demonstrated a 32% increase in aortic atherosclerosis
(11±1% versus 15±4%, P=.01) and an increase in lipid
content (22±8% versus 47±3%, P<.0001) without a
change in macrophage content (10.8±2% versus 11±2%). In
comparison with 20-week-old untreated control mice, 25-week-old apo
A-IMilano/PC–treated mice demonstrated no increase in
aortic atherosclerosis (11±1% versus 10±4%,
P=NS), a 40% reduction in lipid content (22±8% versus
13±8%, P=.01), and a 46% reduction in
macrophage content (10.8±2% versus 5.8±2.9%;
P=.03). Serum cholesterol levels were
markedly elevated in all groups and did not change significantly with
apo A-IMilano/PC or PC only. In vitro, apo
A-IMilano/PC stimulated cholesterol efflux from
cholesterol-loaded FU5AH hepatoma cell lines in a
dose-dependent manner, whereas PC only or PC-free apo
A-IMilano had no effect.
Conclusions—Recombinant A-IMilano/PC prevented
progression of aortic atherosclerosis and reduced lipid
and macrophage content of plaques in apo E–deficient mice
despite severe hypercholesterolemia. Thus,
A-IMilano/PC may have a role in inhibiting progression and
promoting stabilization of atherosclerosis.
© 1998 American Heart Association, Inc.
Basic Science Reports
Effects of Recombinant Apolipoprotein A-IMilano on Aortic Atherosclerosis in Apolipoprotein E–Deficient Mice
Key Words: apolipoproteins • atherosclerosis • hypercholesterolemia
This article has been cited by other articles:
 |
|
 |
|
  C. Parolini, M. Marchesi, P. Lorenzon, M. Castano, E. Balconi, L. Miragoli, L. Chaabane, A. Morisetti, V. Lorusso, B. J. Martin, et al. Dose-related effects of repeated ETC-216 (recombinant apolipoprotein A-I Milano/1-palmitoyl-2-oleoyl phosphatidylcholine complexes) administrations on rabbit lipid-rich soft plaques: in vivo assessment by intravascular ultrasound and magnetic resonance imaging. J. Am. Coll. Cardiol., March 18, 2008; 51(11): 1098 - 1103. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. S. Troutt, W. E. Alborn, M. K. Mosior, J. Dai, A. T. Murphy, T. P. Beyer, Y. Zhang, G. Cao, and R. J. Konrad An apolipoprotein A-I mimetic dose-dependently increases the formation of pre{beta}1 HDL in human plasma J. Lipid Res., March 1, 2008; 49(3): 581 - 587. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Sanossian, J. L. Saver, M. Navab, and B. Ovbiagele High-Density Lipoprotein Cholesterol: An Emerging Target for Stroke Treatment Stroke, March 1, 2007; 38(3): 1104 - 1109. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Wang, B. G. Sharifi, T. Pan, L. Song, A. Yukht, and P. K. Shah Bone Marrow Transplantation Shows Superior Atheroprotective Effects of Gene Therapy With Apolipoprotein A-I Milano Compared With Wild-Type Apolipoprotein A-I in Hyperlipidemic Mice J. Am. Coll. Cardiol., October 3, 2006; 48(7): 1459 - 1468. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Kontush and M. J. Chapman Functionally Defective High-Density Lipoprotein: A New Therapeutic Target at the Crossroads of Dyslipidemia, Inflammation, and Atherosclerosis Pharmacol. Rev., September 1, 2006; 58(3): 342 - 374. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Masson, J.-P. Pais de Barros, Z. Zak, T. Gautier, N. Le Guern, M. Assem, J. W. Chisholm, J. R. Paterniti Jr., and L. Lagrost Human apoA-I expression in CETP transgenic rats leads to lower levels of apoC-I in HDL and to magnification of CETP-mediated lipoprotein changes J. Lipid Res., February 1, 2006; 47(2): 356 - 365. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. Fuster, P. R. Moreno, Z. A. Fayad, R. Corti, and J. J. Badimon Atherothrombosis and High-Risk Plaque: Part I: Evolving Concepts J. Am. Coll. Cardiol., September 20, 2005; 46(6): 937 - 954. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Zhu, G. Wu, W. Zeng, H. Xue, and B. Chen Cysteine mutants of human apolipoprotein A-I: a study of secondary structural and functional properties J. Lipid Res., June 1, 2005; 46(6): 1303 - 1311. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. S. Forrester, R. Makkar, and P.K. Shah Increasing High-Density Lipoprotein Cholesterol in Dyslipidemia by Cholesteryl Ester Transfer Protein Inhibition: An Update for Clinicians Circulation, April 12, 2005; 111(14): 1847 - 1854. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Levin, E. D. Bischoff, C. L. Daige, D. Thomas, C. T. Vu, R. A. Heyman, R. K. Tangirala, and I. G. Schulman Macrophage Liver X Receptor Is Required for Antiatherogenic Activity of LXR Agonists Arterioscler. Thromb. Vasc. Biol., January 1, 2005; 25(1): 135 - 142. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. McAteer, J. E. Schneider, K. Clarke, S. Neubauer, K. M. Channon, and R. P. Choudhury Quantification and 3D Reconstruction of Atherosclerotic Plaque Components in Apolipoprotein E Knockout Mice Using Ex Vivo High-Resolution MRI Arterioscler. Thromb. Vasc. Biol., December 1, 2004; 24(12): 2384 - 2390. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Li, K.-Y. Chyu, J. R. F. Neto, J. Yano, N. Nathwani, C. Ferreira, P. C. Dimayuga, B. Cercek, S. Kaul, and P. K. Shah Differential Effects of Apolipoprotein A-I-Mimetic Peptide on Evolving and Established Atherosclerosis in Apolipoprotein E-Null Mice Circulation, September 21, 2004; 110(12): 1701 - 1705. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Kaul, B. Coin, A. Hedayiti, J. Yano, B. Cercek, K.-Y. Chyu, and P. K. Shah Rapid reversal of endothelial dysfunction in hypercholesterolemic apolipoprotein E-null mice by recombinant apolipoprotein A-IMilano-phospholipid complex J. Am. Coll. Cardiol., September 15, 2004; 44(6): 1311 - 1319. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Trogan, Z. A. Fayad, V. V. Itskovich, J.-G. S. Aguinaldo, V. Mani, J. T. Fallon, I. Chereshnev, and E. A. Fisher Serial Studies of Mouse Atherosclerosis by In Vivo Magnetic Resonance Imaging Detect Lesion Regression After Correction of Dyslipidemia Arterioscler. Thromb. Vasc. Biol., September 1, 2004; 24(9): 1714 - 1719. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. C. Gibson III, C. Hong, H.-H. Chou, H. Yumoto, J. Chen, E. Lien, J. Wong, and C. Attardo Genco Innate Immune Recognition of Invasive Bacteria Accelerates Atherosclerosis in Apolipoprotein E-Deficient Mice Circulation, June 8, 2004; 109(22): 2801 - 2806. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K.-Y. Chyu, S. M. Babbidge, X. Zhao, R. Dandillaya, A. G. Rietveld, J. Yano, P. Dimayuga, B. Cercek, and P. K. Shah Differential Effects of Green Tea-Derived Catechin on Developing Versus Established Atherosclerosis in Apolipoprotein E-Null Mice Circulation, May 25, 2004; 109(20): 2448 - 2453. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Rossoni, M. Gomaraschi, F. Berti, C. R. Sirtori, G. Franceschini, and L. Calabresi Synthetic High-Density Lipoproteins Exert Cardioprotective Effects in Myocardial Ischemia/Reperfusion Injury J. Pharmacol. Exp. Ther., January 1, 2004; 308(1): 79 - 84. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Fazio and M. F. Linton Apolipoprotein AI as Therapy for Atherosclerosis: Does the Future of Preventive Cardiology Include Weekly Injections of the HDL Protein? Mol. Interv., December 1, 2003; 3(8): 436 - 440. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Calabresi, M. Gomaraschi, and G. Franceschini Endothelial Protection by High-Density Lipoproteins: From Bench to Bedside Arterioscler. Thromb. Vasc. Biol., October 1, 2003; 23(10): 1724 - 1731. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. L. Macdonald, T. L. Terry, L. B. Agellon, P. N. Nation, and G. A. Francis Administration of Tyrosyl Radical-Oxidized HDL Inhibits the Development of Atherosclerosis in Apolipoprotein E-Deficient Mice Arterioscler. Thromb. Vasc. Biol., September 1, 2003; 23(9): 1583 - 1588. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Kaul, V. Rukshin, R. Santos, B. Azarbal, C. L. Bisgaier, J. Johansson, V. T. Tsang, K.-Y. Chyu, B. Cercek, J. Mirocha, et al. Intramural Delivery of Recombinant Apolipoprotein A-IMilano/Phospholipid Complex (ETC-216) Inhibits In-Stent Stenosis in Porcine Coronary Arteries Circulation, May 27, 2003; 107(20): 2551 - 2554. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. K. Shah Mechanisms of plaque vulnerability and rupture J. Am. Coll. Cardiol., February 19, 2003; 41(4_Suppl_S): 15S - 22S. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. S. Forrester Prevention of Plaque Rupture: A New Paradigm of Therapy Ann Intern Med, November 19, 2002; 137(10): 823 - 833. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Chiesa, E. Monteggia, M. Marchesi, P. Lorenzon, M. Laucello, V. Lorusso, C. Di Mario, E. Karvouni, R. S. Newton, C. L. Bisgaier, et al. Recombinant Apolipoprotein A-IMilano Infusion Into Rabbit Carotid Artery Rapidly Removes Lipid From Fatty Streaks Circ. Res., May 17, 2002; 90(9): 974 - 980. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. Holvoet, K. Peeters, S. Lund-Katz, A. Mertens, P. Verhamme, R. Quarck, D. Stengel, M. Lox, E. Deridder, H. Bernar, et al. Arg123-Tyr166 Domain of Human ApoA-I Is Critical for HDL-Mediated Inhibition of Macrophage Homing and Early Atherosclerosis in Mice Arterioscler. Thromb. Vasc. Biol., December 1, 2001; 21(12): 1977 - 1983. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. X. Rong, J. Li, E. D. Reis, R. P. Choudhury, H. M. Dansky, V. I. Elmalem, J. T. Fallon, J. L. Breslow, and E. A. Fisher Elevating High-Density Lipoprotein Cholesterol in Apolipoprotein E-Deficient Mice Remodels Advanced Atherosclerotic Lesions by Decreasing Macrophage and Increasing Smooth Muscle Cell Content Circulation, November 13, 2001; 104(20): 2447 - 2452. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. K. Shah, S. Kaul, J. Nilsson, and B. Cercek Exploiting the Vascular Protective Effects of High-Density Lipoprotein and its Apolipoproteins: An Idea Whose Time for Testing Is Coming, Part II Circulation, November 13, 2001; 104(20): 2498 - 2502. [Full Text] [PDF]
|
|
|
|
|
|
P. K. Shah, S. Kaul, J. Nilsson, and B. Cercek Exploiting the Vascular Protective Effects of High-Density Lipoprotein and Its Apolipoproteins: An Idea Whose Time for Testing Is Coming, Part I Circulation, November 6, 2001; 104(19): 2376 - 2383. [Full Text] [PDF]
|
|
|
|
|
|
G. Datta, M. Chaddha, S. Hama, M. Navab, A. M. Fogelman, D. W. Garber, V. K. Mishra, R. M. Epand, R. F. Epand, S. Lund-Katz, et al. Effects of increasing hydrophobicity on the physical-chemical and biological properties of a class A amphipathic helical peptide J. Lipid Res., July 1, 2001; 42(7): 1096 - 1104. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. K. Shah, J. Yano, O. Reyes, K.-Y. Chyu, S. Kaul, C. L. Bisgaier, S. Drake, and B. Cercek High-Dose Recombinant Apolipoprotein A-IMilano Mobilizes Tissue Cholesterol and Rapidly Reduces Plaque Lipid and Macrophage Content in Apolipoprotein E-Deficient Mice : Potential Implications for Acute Plaque Stabilization Circulation, June 26, 2001; 103(25): 3047 - 3050. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. R. Sirtori, L. Calabresi, G. Franceschini, D. Baldassarre, M. Amato, J. Johansson, M. Salvetti, C. Monteduro, R. Zulli, M. L. Muiesan, et al. Cardiovascular Status of Carriers of the Apolipoprotein A-IMilano Mutant : The Limone sul Garda Study Circulation, April 17, 2001; 103(15): 1949 - 1954. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. W. Garber, G. Datta, M. Chaddha, M. N. Palgunachari, S. Y. Hama, M. Navab, A. M. Fogelman, J. P. Segrest, and G. M. Anantharamaiah A new synthetic class A amphipathic peptide analogue protects mice from diet-induced atherosclerosis J. Lipid Res., April 1, 2001; 42(4): 545 - 552. [Abstract] [Full Text]
|
|
|
|
|
|
G. W. Cockerill, T. Y. Huehns, A. Weerasinghe, C. Stocker, P. G. Lerch, N. E. Miller, and D. O. Haskard Elevation of Plasma High-Density Lipoprotein Concentration Reduces Interleukin-1-Induced Expression of E-Selectin in an In Vivo Model of Acute Inflammation Circulation, January 2, 2001; 103(1): 108 - 112. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. THEILMEIER, B. DE GEEST, P. P. VAN VELDHOVEN, D. STENGEL, C. MICHIELS, M. LOX, M. LANDELOOS, M. J. CHAPMAN, E. NINIO, D. COLLEN, et al. HDL-associated PAF-AH reduces endothelial adhesiveness in apoE-/- mice FASEB J, October 1, 2000; 14(13): 2032 - 2039. [Abstract] [Full Text]
|
|
|
|
|
|
P. G. Frank and Y. L. Marcel Apolipoprotein A-I: structure;-function relationships J. Lipid Res., June 1, 2000; 41(6): 853 - 872. [Abstract] [Full Text]
|
|
|
|
|
|
K. J. Williams, R. Scalia, K. D. Mazany, W. V. Rodrigueza, and A. M. Lefer Rapid Restoration of Normal Endothelial Functions in Genetically Hyperlipidemic Mice by a Synthetic Mediator of Reverse Lipid Transport Arterioscler. Thromb. Vasc. Biol., April 1, 2000; 20(4): 1033 - 1039. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K.-Y. Chyu, P. Dimayuga, J. Zhu, J. Nilsson, S. Kaul, P. K. Shah, and B. Cercek Decreased Neointimal Thickening After Arterial Wall Injury in Inducible Nitric Oxide Synthase Knockout Mice Circ. Res., December 3, 1999; 85(12): 1192 - 1198. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. K. Spady Reverse Cholesterol Transport and Atherosclerosis Regression Circulation, August 10, 1999; 100(6): 576 - 578. [Full Text] [PDF]
|
|
|
|
|
|
M. Eriksson, L. A. Carlson, T. A. Miettinen, and B. Angelin Stimulation of Fecal Steroid Excretion After Infusion of Recombinant Proapolipoprotein A-I : Potential Reverse Cholesterol Transport in Humans Circulation, August 10, 1999; 100(6): 594 - 598. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. K Shah Role of inflammation and metalloproteinases in plaque disruption and thrombosis Vascular Medicine, August 1, 1998; 3(3): 199 - 206. [Abstract] [PDF]
|
|